Early studies focused on septic shock pathophysiology (Am J Physiol 1988; Chest 1990), the role of endotoxemia (J Clin Invest 1989; J Exp Med 1989; Chest 1991; N Engl J Med 1993; Infect Immun 1996), and the efficacy of various anti-endotoxin therapies (Antimicrob Agents Chemother 1989) including lipid A analogs (J Clin Invest 1987; Pharm Res 1990) and antibodies (JAMA 1993; J Infect Dis 1994). Nitric oxide (&#729;NO) was examined as an important mediator of septic shock (Crit Care Med 1993; JAMA 1996). Non-selective &#729;NO synthase inhibitors were found to be sometimes toxic and never beneficial (J Exp Med 1992; Crit Care Med 1998; Am J Respir Crit Care Med 1998). Increased &#729;NO production in normal volunteers challenged with endotoxin was blocked by ibuprofen, but blood pressure was unaffected, suggesting that other mechanisms compensated to maintain vasodilation (J Pharmacol Exp Ther 1999). Severity of illness (risk of death) influenced the therapeutic efficacy of anti-inflammatory agents in septic shock (Am J Respir Crit Care Med 2002). This finding was used by the FDA to re-analyze the PROWESS trial of rhAPC (Xigris) and led to initial approval only for patients with a high risk of death. The administration of L-arginine without or with N-acetylcysteine in a canine model of septic shock was found to be harmful (Crit Care Med 2006). L-arginine is a common component of immunonutrition formulas that are marketed for use in critically ill patients. Our canine septic shock model was redeveloped to better balance animal welfare and scientific relevance. Both specific and supportive titrated therapies routinely used in septic patients were fully integrated into the model to provide a more realistic setting to evaluate therapies for sepsis (Am J Physiol Heart Circ Physiol 2007). Whether risk of death altered the effects of hydrocortisone was investigated in a mouse model of E. coli pneumonia (Intensive Care Med 2008). Intra-aortic balloon counterpulsation was demonstrated to prolong survival in a hypodynamic canine model of Staphylococcus aureas pneumonia induced septic shock (Crit Care Med 2009). Counterpulsation support of left ventricular function might improve survival in episodes of septic shock associated with compromised cardiac output. A low cardiac output is seen in 10 to 20 percent of adults and up to 50 percent of children with septic shock. The U.S. Critical Illness and Injury Trials Group (USCIITG; http://www.usciitg.org/) was founded to create a clinical research framework that can reduce the barriers to investigation (Crit Care Med 2009). A meta-analysis of bundled care for septic shock demonstrated consistent and significant improvement in survival and antibiotic use. Use of other bundle components changed heterogeneously across studies, making their impact on survival uncertain (Crit Care Med 2010). SB203580, a p38 inhibitor, improved cardiac function but worsened lung injury and survival during E. coli pneumonia in mice (J Trauma 2010). Anthrax lethal toxin (LeTx)-induced shock was found to differ substantially from LPS challenge in rats. Fluids and vasopressors, standard approaches to septic shock, were harmful (Crit Care Med 2009). Notably, anthrax infection fails to induce NO&#729; synthase 2, due to a LeTx-mediated truncation of inflammatory signaling inside cells. In sedated canines receiving mechanical ventilation, edema toxin increased mortality when added to equimolar lethal toxin challenges (J Infect Dis 2010). Heparin in a mouse model of E. coli pneumonia failed to improve lung injury or survival Crit Care Med 2011). Corticosteroid regimens that activate both mineralocorticoid (MR) and glucocorticoid receptors (GR) consistently reverse vasopressor-dependent hypotension in septic shock, but have variable effects on survival. In a canine model of S. aureus pneumonia-induced septic shock, selective agonists of MR and GR were examined separately. Mineralocorticoid was only beneficial if given prophylactically, while glucocorticoid was most beneficial when given close to the onset of infection (Crit Care Med 2012). Stress dose corticosteroids were only beneficial in cases of sepsis with high risk for death (Intensive Care Med 2012). Tigecycline was found to be associated with increased mortality and non-cure rates. Effects were not isolated to type of infection or comparator antibiotic regimen, and the impact on survival remained significant when limited to trials of approved indications (Clin Infect Dis 2012). These findings prompted the revision existing guidelines. Staphylococcal enterotoxin including B (SEB) can trigger a lethal super antigen-mediated cytokine storm. These exotoxins contribute to the high mortality of S. aureus sepsis and also pose a threat as potential bioweapons. Using an aerosolized-toxin, mouse model, globally profile gene-expression changes across multiple organs implicated a host-wide IFN-response in SEB-induced death (PLoS One 2014). These results suggest that therapies aimed at IFN innate immunity may improve outcome in toxic shock syndromes. The pathophysiology of the hypothalamic-pituitary-adrenal (HPA) axis in sepsis has not been well characterized. In order to understand the contribution of the responsiveness of the HPA axis and the relative levels of glucocorticoids and mineralcorticoids, a project in collaboration with the Natanson canine lab characterized the hypothalamic-pituitary-adrenal (HPA) function serially over five days in 101 canines with severe Staphylococcus aureus pneumonia. During septic shock, the serial measurements and provocative testing over a well-defined timeline was able to demonstrate a strong relationship between HPA axis function and prognosis. HPA axis unresponsiveness and high aldosterone levels identified a septic shock subpopulation with poor outcomes that may have the greatest potential to benefit from new therapies (Am J Physiol Endocrinol Metab 2014). Infections caused by multidrug-resistant and extensively drug-resistant gram-negative organisms may be the greatest emerging threat to critically ill patients worldwide. Carbapenem resistance increases the risk of death from gram-negative infections. Intravenous colistin administration for more than 3 consecutive days identified a severely ill population with a high probability of having culture-confirmed carbapenem resistant gram-negative infections, particularly those caused by extensively drug-resistant bacteria. Colistin-cases at 40 academic medical centers nearly trebled over 7 years (Clin Infect Dis 2015).